Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection

Tracy T. Chow, Xiaoyu Shi, Jen-Hsuan Wei, Juan Guan, Guido Stadler, Bo Huang and Elizabeth H. Blackburn ()
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Tracy T. Chow: University of California, San Francisco
Xiaoyu Shi: University of California, San Francisco
Jen-Hsuan Wei: University of California, San Francisco
Juan Guan: University of California, San Francisco
Guido Stadler: Berkeley Lights Inc
Bo Huang: University of California, San Francisco
Elizabeth H. Blackburn: University of California, San Francisco

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

Date: 2018
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DOI: 10.1038/s41467-018-05840-y

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